CN104311453A - Preparation method of anti-hypertensive drug - Google Patents
Preparation method of anti-hypertensive drug Download PDFInfo
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Abstract
The invention provides a preparation method of an anti-hypertensive drug. Specifically the invention provides a novel intermediate: 2-ethoxy-1-{[2'-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3-yl)biphenyl-4-yl]methyl}-1H-benzoimidazole-7-carboxylic acid (Azilsartan). The intermediate is represented by the formula A, wherein in the formula the X represents an H atom or a halogen atom. The Azilsartan can be rapidly and conveniently prepared through the prepared intermediate represented by the formula A. Moreover, the preparation method has the advantages of short reaction route, less by products, high total yield, and mild conditions, and is suitable for industrial production of Azilsartan.
Description
Technical field
The present invention relates to technical field of pharmaceutical chemistry, be specifically related to a kind of antihypertensive drug 2-oxyethyl group-1-{ [2 '-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3-base) xenyl-4-base] methyl } synthetic method of-1H-benzoglyoxaline-7-carboxylic acid (I).
Background technology
Azilsartan is a kind of medicine for the treatment of vascular hypertension, this medicine reaches by blocking the activity of vasoconstrictionⅡ acceptor the effect reduced blood pressure, this medicine, as a kind of Angiotensin Ⅱ receptor antagonist, can be used alone or use together with other Altace Ramipril.This medical instrument is effective good, and curative effect is good, bioavailability advantages of higher, also can reduce the risk of cardiovascular disorder and diabetes by number of mechanisms.Azilsartan obtains listing in Japan in January, 2012 first by the pharmacy of military field.
Its chemical structure is as follows:
According to existing document, the synthetic route preparing Azilsartan has as follows:
Route one:
Route two:
Route three:
Route one is the synthetic route of the Azilsartan (I) of report on patent CN103880830, and second route is derived from document (Org.Process Res.Dev.2013,17,77-86) and patent CN201210254405.These two lines are similar, are all to adopt ethoxybenzoimidazole-7-carboxylate methyl ester as reaction raw materials.Route one is with 2-cyano group-4'-methyl diphenyl for raw material, by oximate, amidation, Guan Huan, bromination, amination and hydrolysis totally six steps obtain target compound; Route two is first by replacing, oximate, and amidation, totally five steps of closing ring and hydrolysis prepare Azilsartan.These two synthetic route amidations all adopt highly toxic product Vinyl chloroformate to do raw material; And 2-cyano group-4'-methyl diphenyl and 2-cyano group-4'-bromomethylbiphenyl cost of material higher, the not easily shortcoming such as acquisition.
Route three is document [Chinese Journal of Pharmaceuticals, 2010,41 (12), 881-883] and WO2006015134 introduce synthesis a kind of Azilsartan synthetic route, this route process cycle is long, complex operation, by product is more, and process overall yields is low, is 14.2%; And this reaction uses comparatively dangerous industrial chemicals sodiumazide and highly toxic product Vinyl chloroformate to do reaction raw materials, is unfavorable for safety and the environment protection of suitability for industrialized production.
In sum, it is short that this area still lacks a kind of reaction scheme, simple to operate, and by product is few, the Azilsartan preparation method that total recovery is high.
Summary of the invention
The invention provides a kind of reaction scheme short, simple to operate, by product is few, the Azilsartan preparation method that total recovery is high.
A first aspect of the present invention, provides a kind of as shown in the formula the compound shown in A:
Wherein, X is selected from lower group: halogen; Preferably, X is Cl or Br.
A second aspect of the present invention, provides a kind of preparation method of formula A compound as described in the first aspect of the invention, comprises step:
(2) in inert solvent, react with formula (III) compound and halide reagent, obtain formula A compound:
In formula, X is halogen; Preferably, X is Cl or Br.
In another preference, in described step (2), described halide reagent is selected from lower group: chlorine, NCS, sulfur oxychloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, trichloroisocyanuric acid, or its combination; Preferred NCS, trichloroisocyanuric acid, or its combination.
In another preference, in described step (2), described inert solvent is selected from lower group: methylene dichloride, tetrahydrofuran (THF), toluene, dimethylbenzene, dioxane, normal heptane, normal hexane, or its combination; Preferred methylene dichloride.
In another preference, in described step (2), described temperature of reaction is-10 ~ 60 DEG C, is preferably-5 ~ 30 DEG C.
In another preference, in described step (2), add halide reagent at-5 ~ 10 DEG C after, react at 10 ~ 60 DEG C.
In another preference, in described step (2), the mol ratio of formula (III) compound and halide reagent is 1:0.5 ~ 2.
In another preference, in described step (2), the described reaction times is 1-4h.
In another preference, described method also comprises step:
(1) in inert solvent, with formula (II) compound and oximate reagent react, formula (III) compound is obtained:
Preferably, described oximate reagent is selected from lower group: oxammonium hydrochloride, phosphatic hydroxylamine, hydrogen peroxide/ammonium chloride, hydrogen peroxide/ammonium acetate, or its combination; Preferred oxammonium hydrochloride, phosphatic hydroxylamine, or its combination.
In another preference, in described step (1), described reaction is carried out under alkaline catalysts exists; Preferably, described alkaline catalysts is selected from lower group: salt of wormwood, sodium carbonate, sodium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, or its combination; Preferred sodium hydroxide, potassium hydroxide, or its combination.
In another preference, in described step (1), described inert solvent is selected from lower group: water, methyl alcohol, ethanol, HTF, dioxane, methylene dichloride, or its combination; Preferably water, ethanol, or its combination.
In another preference, in described step (1), described temperature of reaction is 0 ~ 50 DEG C, is preferably 10 ~ 40 DEG C.
In another preference, in described step (1), described formula (II) compound and the mol ratio of oximate reagent are 1:0.5-2.
In another preference, in described step (1), the described reaction times is 1-5h.
A third aspect of the present invention, provide the preparation method of a kind of formula (V) compound, described method comprises step:
(3) in inert solvent, react with formula A compound and cyanate, obtain formula (V) compound;
Wherein, the definition of X is as described in first aspect present invention; Preferably, X is Cl.
In another preference, in described step (3), described cyanate is selected from lower group: potassium cyanate, Zassol, or its combination; Preferred potassium cyanate.
In another preference, in described step (3), described inert solvent is selected from lower group: acetone, methylene dichloride, toluene, dimethylbenzene, methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), dioxane, or its combination; Preferred acetone.
In another preference, described step (3) is carried out in anhydrous conditions.
In another preference, in described step (3), described temperature of reaction is 0 ~ 60 DEG C, is preferably 10 ~ 40 DEG C.
In another preference, in described step (3), the mol ratio of described formula A compound and cyanate is 1:0.5 ~ 2.
In another preference, in described step (3), the described reaction times is 5-20h.
A fourth aspect of the present invention, provides a kind of preparation method as shown in the formula the compound Azilsartan shown in (I):
It is characterized in that, comprise step:
(3) in inert solvent, react with formula (IV) compound and cyanate, obtain formula (V) compound;
with
With formula (V) preparation of compounds of formula (I) compound.
In another preference, described method also comprises step:
(4) in inert solvent, react with formula (V) compound and bromide reagent, obtain formula (VI) compound;
(5) in inert solvent, react with formula (VI) and formula (VII) compound, obtain formula (VIII) compound;
(6) in inert solvent, be hydrolyzed with formula (VIII) compound, obtain formula (I) compound;
Preferably, described step (5) is carried out under base catalysis;
Preferably, described step (6) is carried out under base catalysis.
In another preference, in described step (4), described inert solvent is selected from lower group: tetracol phenixin, methylene dichloride, tetrahydrofuran (THF), toluene, dimethylbenzene, dioxane, normal heptane, normal hexane, or its combination; Preferred tetracol phenixin, methylene dichloride.
In another preference, in described step (4), described reaction is carried out under initiator exists; Preferably, described initiator is selected from lower group: Diisopropyl azodicarboxylate (AIBN), 2,2'-Azobis(2,4-dimethylvaleronitrile) (ABVN), azo-bis-iso-dimethyl (AIBME), benzoyl peroxide (BPO), tertbutyl peroxide (TBHP); Preferred Diisopropyl azodicarboxylate (AIBN), benzoyl peroxide (BPO).
In another preference, in described step (4), described bromide reagent is selected from lower group: bromine, NBS, C5H6Br2N2O2,5,5-dibromo barbituric acids (DBBA), 1, the bromo-1,3,5-triazines-2 of 3-bis-, 4,6-triketone (DBI), or its combination; Preferred NBS, DBI, or its combination.
In another preference, in described step (4), described temperature of reaction is 60 ~ 100 DEG C, is preferably 60 ~ 90 DEG C.
In another preference, in described step (5), described inert solvent is selected from lower group: ethanol, methyl alcohol, methylene dichloride, DMF, acetonitrile, toluene, dimethylbenzene, dioxane, THF, or its combination; Be preferably ethanol and/or methyl alcohol.
In another preference, in described step (5), described alkaline catalysts is selected from lower group: salt of wormwood, sodium carbonate, sodium bicarbonate, cesium carbonate, or its combination; Preferred salt of wormwood and/or sodium carbonate.
In another preference, in described step (5), described temperature of reaction is 10 ~ 150 DEG C, is preferably 50 ~ 100 DEG C.
In another preference, in described step (6), described inert solvent is selected from lower group: water, methyl alcohol, ethanol, tetrahydrofuran (THF), dioxane, or its combination; Preferably water.
In another preference, in described step (6), described alkaline catalysts is selected from lower group: hydrated barta, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, or its combination; Be preferably sodium hydroxide and/or potassium hydroxide.
In another preference, in described step (6), described temperature of reaction is 50 ~ 100 DEG C, is preferably 60 ~ 90 DEG C.
In another preference, described method also comprises step:
(1) in inert solvent, with formula (II) compound and oximate reagent react, formula (III) compound is obtained:
(2) in inert solvent, react with formula (III) compound and chlorination reagent, obtain formula (IV) compound:
In another preference, in described step (1), described reaction is carried out under alkaline catalysts exists; Preferably, described alkaline catalysts is selected from lower group: salt of wormwood, sodium carbonate, sodium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, or its combination; Preferred sodium hydroxide, potassium hydroxide, or its combination.
In another preference, in described step (1), described inert solvent is selected from lower group: water, methyl alcohol, ethanol, HTF, dioxane, methylene dichloride, or its combination; Preferably water, ethanol, or its combination.
In another preference, in described step (1), described temperature of reaction is 0 ~ 50 DEG C, is preferably 10 ~ 40 DEG C.
In another preference, in described step (1), described formula (II) compound and the mol ratio of oximate reagent are 1:0.5-2.
In another preference, in described step (1), the described reaction times is 1-5h.
In another preference, in described step (2), described halide reagent is selected from lower group: chlorine, NCS, sulfur oxychloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, trichloroisocyanuric acid, or its combination; Preferred NCS, trichloroisocyanuric acid, or its combination.
In another preference, in described step (2), described inert solvent is selected from lower group: methylene dichloride, tetrahydrofuran (THF), toluene, dimethylbenzene, dioxane, normal heptane, normal hexane, or its combination; Preferred methylene dichloride.
In another preference, in described step (2), described temperature of reaction is-10 ~ 60 DEG C, is preferably-5 ~ 30 DEG C.
In another preference, in described step (2), add halide reagent at-5 ~ 10 DEG C after, react at 10 ~ 60 DEG C.
In another preference, in described step (2), the mol ratio of formula (III) compound and halide reagent is 1:0.5 ~ 2.
In another preference, in described step (2), the described reaction times is 1-4h.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Embodiment
The present inventor is through long-term and deep research, be surprised to find that, by preparing such as formula the intermediate shown in (A) thus preparing Azilsartan, Azilsartan can be prepared with higher yield and very short route, and reaction conditions is gentle, by product is few, is suitable for very much suitability for industrialized production Azilsartan.Based on above-mentioned discovery, contriver completes the present invention.
Term
As used herein, term " halogen " refers to fluorine, chlorine, bromine, iodine.
Term " Azilsartan " and " 2-oxyethyl group-1-{ [2'-(5-carbonyl-4; 5-dihydro-1; 2,4-oxadiazole-3-base) xenyl-4-base] methyl }-1H-benzoglyoxaline-7-carboxylic acid " are used interchangeably, and all refer to the compound with structure shown in formula (I):
Formula A compound and preparation thereof
The invention provides a kind of as shown in the formula the compound shown in A:
Wherein, X is selected from lower group: halogen; Preferably, X is Cl or Br.
The preparation method of described formula (IV) compound comprises step:
(2) in inert solvent, react with formula (III) compound and halide reagent, obtain formula A compound;
In formula, X is halogen.
Preferably, in described step (2), described halide reagent is selected from lower group: chlorine, NCS, sulfur oxychloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, trichloroisocyanuric acid, or its combination; Preferred NCS, trichloroisocyanuric acid, or its combination.
In described step (2), described inert solvent is not particularly limited, preferred described inert solvent comprises the solvent that (but being not limited to) is selected from lower group: methylene dichloride, tetrahydrofuran (THF), toluene, dimethylbenzene, dioxane, normal heptane, normal hexane, or its combination; Preferred methylene dichloride.
Preferably, in described step (2), described temperature of reaction is-10 ~ 60 DEG C, is preferably-5 ~ 30 DEG C.
In another preference, the preparation method of described formula A compound also comprises step:
(1) in inert solvent, with formula (II) compound and oximate reagent react, formula (III) compound is obtained:
Described oximate reagent is preferably selected from the oximate reagent of lower group: oxammonium hydrochloride, phosphatic hydroxylamine, hydrogen peroxide/ammonium chloride, hydrogen peroxide/ammonium acetate, or its combination; Preferred oxammonium hydrochloride, phosphatic hydroxylamine, or its combination.
In another preference, in described step (1), described reaction is carried out under alkaline catalysts exists; Preferably, described alkaline catalysts is selected from lower group: salt of wormwood, sodium carbonate, sodium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, or its combination; Preferred sodium hydroxide, potassium hydroxide, or its combination.
In described step (1), described inert solvent is not particularly limited, and can be polar solvent or polar solvent mixture.Preferred described inert solvent comprises the solvent that (but being not limited to) is selected from lower group: water, methyl alcohol, ethanol, HTF, dioxane, methylene dichloride, or its combination; Preferably water, ethanol, or its combination.
Preferably, in described step (1), described temperature of reaction is 0 ~ 50 DEG C, is preferably 10 ~ 40 DEG C.
In another preference, in described step (1), described formula (II) compound and the mol ratio of oximate reagent are 1:0.5-2.
The preparation of Azilsartan intermediate
Present invention also offers a kind of preparation method of Azilsartan intermediate formula (V) compound, described method comprises step:
(3) in inert solvent, react with formula A compound and cyanate, obtain formula (V) compound;
Wherein, X is halogen, and preferably, X is Cl.
Preferably, in described step (3), described cyanate is selected from lower group: potassium cyanate, Zassol, or its combination; Preferred potassium cyanate.
In described step (3), described inert solvent is not particularly limited, preferred described inert solvent comprises the solvent that (but being not limited to) is selected from lower group: acetone, methylene dichloride, toluene, dimethylbenzene, methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), dioxane, or its combination; Preferred acetone.
In another preference, in described step (3), described temperature of reaction is 0 ~ 60 DEG C, is preferably 10 ~ 40 DEG C.
Described formula (V) compound may be used for preparing Azilsartan (i.e. formula (I) compound), and preparation method has no particular limits, and those skilled in the art can be prepared with reference to prior art.A kind of typical preparation method is the synthetic route as Chinese application publication number CN103880830 report.
The preparation of Azilsartan
Present invention also offers a kind of preparation method as shown in the formula the compound Azilsartan shown in (I):
It is characterized in that, comprise step:
(3) in inert solvent, react with formula (IV) compound and cyanate, obtain formula (V) compound;
with
With formula (V) preparation of compounds of formula (I) compound.
In another preference, described method also comprises step:
(4) in inert solvent, react with formula (V) compound and bromide reagent, obtain formula (VI) compound;
(5) in inert solvent, react with formula (VI) and formula (VII) compound, obtain formula (VIII) compound;
(6) in inert solvent, be hydrolyzed with formula (VIII) compound, obtain formula (I) compound;
Preferably, described step (5) is carried out under base catalysis;
Preferably, described step (6) is carried out under base catalysis.
In another preference, in described step (4), described inert solvent is selected from lower group: tetracol phenixin, methylene dichloride, tetrahydrofuran (THF), toluene, dimethylbenzene, dioxane, normal heptane, normal hexane, or its combination; Preferred tetracol phenixin, methylene dichloride.
In another preference, in described step (4), described reaction is carried out under initiator exists; Preferably, described initiator is selected from lower group: Diisopropyl azodicarboxylate (AIBN), 2,2'-Azobis(2,4-dimethylvaleronitrile) (ABVN), azo-bis-iso-dimethyl (AIBME), benzoyl peroxide (BPO), tertbutyl peroxide (TBHP); Preferred Diisopropyl azodicarboxylate (AIBN), benzoyl peroxide (BPO).
In another preference, in described step (4), described bromide reagent is selected from lower group: bromine, NBS, C5H6Br2N2O2,5,5-dibromo barbituric acids (DBBA), 1, the bromo-1,3,5-triazines-2 of 3-bis-, 4,6-triketone (DBI), or its combination; Preferred NBS, DBI, or its combination.
In another preference, in described step (4), described temperature of reaction is 60 ~ 100 DEG C, is preferably 60 ~ 90 DEG C.
In another preference, in described step (5), described inert solvent is selected from lower group: ethanol, methyl alcohol, methylene dichloride, DMF, acetonitrile, toluene, dimethylbenzene, dioxane, THF, or its combination; Be preferably ethanol and/or methyl alcohol.
In another preference, in described step (5), described alkaline catalysts is selected from lower group: salt of wormwood, sodium carbonate, sodium bicarbonate, cesium carbonate, or its combination; Preferred salt of wormwood and/or sodium carbonate.
In another preference, in described step (5), described temperature of reaction is 10 ~ 150 DEG C, is preferably 50 ~ 100 DEG C.
In another preference, in described step (6), described inert solvent is selected from lower group: water, methyl alcohol, ethanol, tetrahydrofuran (THF), dioxane, or its combination; Preferably water.
In another preference, in described step (6), described alkaline catalysts is selected from lower group: hydrated barta, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, or its combination; Be preferably sodium hydroxide and/or potassium hydroxide.
In another preference, in described step (6), described temperature of reaction is 50 ~ 100 DEG C, is preferably 60 ~ 90 DEG C.
In one preferred embodiment of the invention, described method also comprises step:
(1) in inert solvent, with formula (II) compound and oximate reagent react, formula (III) compound is obtained:
(2) in inert solvent, react with formula (III) compound and halide reagent, obtain formula (IV) compound:
In above steps, the reaction times has no particular limits, and can judge reaction end by the method (as TLC method) that this area is conventional.
In the preferred embodiment of the present invention, the condition that each step is concrete is as follows:
(1) preparation of compound (III):
Appropriate alkaline catalysts and appropriate oximate reagent are dissolved in suitable solvent, abundant mixing, and then add 2-aldehyde radical-4 '-methyl diphenyl (II), react at suitable temperature, after having reacted, compound (III) can be obtained through suitable process.
Wherein, suitable solvent is water, methyl alcohol, ethanol, HTF, dioxane, methylene dichloride; Preferably water, ethanol; Appropriate oximate reagent is oxammonium hydrochloride, phosphatic hydroxylamine, hydrogen peroxide/ammonium chloride, hydrogen peroxide/ammonium acetate, preferred oxammonium hydrochloride, phosphatic hydroxylamine; Suitable salt of wormwood, sodium carbonate, sodium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, preferred sodium hydroxide, potassium hydroxide; Add under optimal temperature in batches; Temperature of reaction is 0 ~ 50 DEG C, is preferably 10 ~ 40 DEG C.
(2) preparation of compound (IV):
Compound (III) is dissolved in applicable solvent, at suitable temperature, add appropriate chlorination reagent, and reaction obtains compound (IV) at a suitable temperature.
Wherein suitable solvent is methylene dichloride, tetrahydrofuran (THF), toluene, dimethylbenzene, dioxane, normal heptane, normal hexane, preferred methylene dichloride; Suitable chlorination reagent is chlorine, NCS, sulfur oxychloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, trichloroisocyanuric acid, preferred NCS, trichloroisocyanuric acid; Slowly add under optimal temperature in batches; Temperature of reaction is-10 ~ 60 DEG C, is preferably-5 ~ 30 DEG C.
(3) preparation of compound (V):
Compound (IV) and cyanic acid salt reagent being dissolved in suitable solvent, at suitable temperature, carrying out Guan Huan, obtaining compound (V) through suitably processing.
Wherein suitable solvent is acetone, methylene dichloride, toluene, dimethylbenzene, methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), dioxane, preferred acetone; Suitable cyanate is potassium cyanate, Zassol, preferred isocyanic acid potassium; Add under optimal temperature in batches; Temperature of reaction is 0 ~ 60 DEG C, is preferably 10 ~ 40 DEG C.
(4) preparation of compound (VI):
Compound (V) is dissolved in applicable solvent, at suitable temperature, adds appropriate initiator and bromide reagent successively, and complete reaction at a suitable temperature, obtain compound (VI).
Wherein suitable solvent is tetracol phenixin, methylene dichloride, tetrahydrofuran (THF), toluene, dimethylbenzene, dioxane, normal heptane, normal hexane, preferred tetracol phenixin, methylene dichloride; Suitable initiator is Diisopropyl azodicarboxylate (AIBN), 2,2'-Azobis(2,4-dimethylvaleronitrile) (ABVN), azo-bis-iso-dimethyl (AIBME), benzoyl peroxide (BPO), tertbutyl peroxide (TBHP) etc., preferred Diisopropyl azodicarboxylate (AIBN), benzoyl peroxide (BPO); Suitable bromide reagent is bromine, NBS, C5H6Br2N2O2,5,5-dibromo barbituric acid (DBBA), 1,3-bis-bromo-1,3,5-triazines-2,4,6-triketone (DBI), preferred NBS, DBI; Slowly add under optimal temperature in batches; Temperature of reaction is 60 ~ 100 DEG C, is preferably 60 ~ 90 DEG C.
(5) preparation of compound (VIII):
Compound (VI) and ethoxybenzoimidazole-7-carboxylate methyl ester (VII) are dissolved in suitable solvent, add suitable alkali as a catalyst, react at a proper temperature, just can obtain compound (VIII) through suitable aftertreatment.
Wherein suitable reagent is ethanol, methyl alcohol, methylene dichloride, DMF, acetonitrile, toluene, dimethylbenzene, dioxane, THF, preferred alcohol, methyl alcohol; Suitable catalyzer is salt of wormwood, sodium carbonate, sodium bicarbonate, cesium carbonate, preferred salt of wormwood, sodium carbonate; Add under optimal temperature in batches; Temperature of reaction is 10 ~ 150 DEG C, is preferably 50 ~ 100 DEG C.
(6) preparation of Azilsartan (I):
Compound (VIII) is dissolved in a suitable solvent, adds suitable catalyzer and be hydrolyzed, finally obtain compound Azilsartan (I).
Wherein suitable reagent is water, methyl alcohol, ethanol, tetrahydrofuran (THF), dioxane, preferably water; Suitable catalyzer is for being hydrated barta, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, preferred sodium hydroxide, potassium hydroxide; Add under optimal temperature in batches; Temperature of reaction is 50 ~ 100 DEG C, is preferably 60 ~ 90 DEG C.
Major advantage of the present invention
A kind of novel synthesis Azilsartan route of research and design of the present invention, compared with prior art, the present invention has route novelty, easy and simple to handle, and raw material is totally easy to get, and environmental safety is friendly, yield advantages of higher, is therefore applicable to industrial production Azilsartan.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise per-cent and number calculate by weight.
Embodiment 1:
(1) preparation of compound (III):
Under room temperature, by hydroxylamine hydrochloride solution (10.63g, 152.87mmol, water 50ml) add in 20% aqueous sodium hydroxide solution (25mL), and stir 15min at such a temperature, then add 2-aldehyde radical-4 '-methyl diphenyl (II) (20.0g, 101.92mmol), and continuation reaction 2h, TLC detection reaction completes at such a temperature.Suction filtration, filter cake washes three times, and dry to obtain compound (III) 21.1g, yield is 98%.
(2) preparation of compound (IV):
Compound (III) (21.0g is added to 1L round-bottomed flask, 99.41mmol), DMF (10mL) and DCM (500mL), be chilled to 0 DEG C, slowly add NCS (14.6g, 109.35mmol), reinforced complete, be placed in stirred at ambient temperature 2h, TLC detection reaction completes.Reaction solution is poured in water (300mL), stir 15min, get organic phase, wash successively with water (200mL) and saturated aqueous common salt (200mL), anhydrous sodium sulfate drying, revolves desolventizing, obtain product compound (IV) 22.47g, yield is 92%.
1H-NMR(400MHz,DMSO-d6):δ9.20(s,1H),7.73-7.65(m,2H),7.55-7.47(m,2H),7.35-7.24(m,4H),2.36(s,3H).C
14H
12ClNOCalcd:245.0607,found:245.0612
(3) preparation of compound (V):
By compound (IV) (22.0g, 89.54mmol), potassium cyanate (10.90g, 134.31mmol) and anhydrous propanone (300mL), complete in stirred at ambient temperature 10h, TLC detection reaction.Poured into by reaction solution in 600mL water, have a large amount of solid to separate out, suction filtration, a small amount of water washing, obtain compound (V) 18.63g, yield is 82.5%.
(4) preparation of compound (VI):
By compound (V) (18.0g, 71.35mmol) be dissolved in tetracol phenixin (300mL), then Diisopropyl azodicarboxylate (0.59g is added successively, 3.57mmol), NBS (12.70g, 71.35mmol), heating reflux reaction 1h, TLC detects, and reaction completes.Cold cut, to room temperature, is poured in water (200mL), is got organic phase, washes twice with water (2x100mL), and revolve desolventizing and obtain compound (VI) 21.03g, yield is 89.0%.
(5) preparation of compound (VIII):
500ml round-bottomed flask adds compound (VI) (21.0g, 63.41mmol), compound (VII) (13.96g, 63.41mmol) with ethanol (200mL), and stir 15min, then add sodium carbonate (13.44g, 126.82mmol), be heated with stirring to backflow 5h, TLC to detect, reaction completes.Reclaim ethanol, residue mixes with water (100mL) pulls an oar, and filters, uses a small amount of water washing, and dry, obtain compound (VIII) 26.85g, yield is 90.0%.
(6) preparation of Azilsartan (I):
250ml round-bottomed flask adds compound (VIII) (25.0g, 53.14mmol) with water (130mL), stir, slowly add 10% sodium hydroxide solution (42.5mL, 106.28mmol), be heated to 75 DEG C of reaction 1h, TLC detection reaction complete.Be chilled to room temperature and be placed in ice-water bath, being down to 0 DEG C, slowly adding 1N hydrochloric acid under stirring to pH=3.Filter, filter cake obtains white solid through dehydrated alcohol recrystallization, is Azilsartan (I) 22.56g, yield 93%.
Embodiment 2
(1) preparation of compound (III):
Under room temperature, by hydroxylamine hydrochloride solution (10.63g, 152.87mmol, water 50ml) add in 20% aqueous sodium hydroxide solution (25mL), and stir 15min at such a temperature, then add 2-aldehyde radical-4 '-methyl diphenyl (II) (20.0g, 101.92mmol), and continuation reaction 2h, TLC detection reaction completes at such a temperature.Suction filtration, filter cake washes three times, and dry to obtain compound (III) 20.9g, yield is 97%.
(2) preparation of compound (IV):
Compound (III) (20.5g is added to 1L round-bottomed flask, 97.04mmol), DMF (10mL) and DCM (500mL), be chilled to 0 DEG C, slowly add NCS (14.25g, 106.74mmol), reinforced complete, be placed in stirred at ambient temperature 2h, TLC detection reaction completes.Reaction solution is poured in water (300mL), stir 15min, get organic phase, wash successively with water (200mL) and saturated aqueous common salt (200mL), anhydrous sodium sulfate drying, revolves desolventizing, obtain product compound (IV) 21.46g, yield is 90.0%.
1H-NMR(400MHz,DMSO-d6):δ9.20(s,1H),7.73-7.65(m,2H),7.55-7.47(m,2H),7.35-7.24(m,4H),2.36(s,3H).C
14H
12ClNO?Calcd:245.0607,found:245.0612
(3) preparation of compound (V):
By compound (IV) (21.0g, 85.47mmol), potassium cyanate (10.40g, 128.21mmol) and anhydrous propanone (300mL), complete in stirred at ambient temperature 10h, TLC detection reaction.Poured into by reaction solution in 600mL water, have a large amount of solid to separate out, suction filtration, a small amount of water washing, obtain compound (V) 18.11g, yield is 84.0%.
(4) preparation of compound (VI):
By compound (V) (18.0g, 71.35mmol) be dissolved in tetracol phenixin (300mL), then Diisopropyl azodicarboxylate (0.59g is added successively, 3.57mmol), NBS (12.70g, 71.35mmol), heating reflux reaction 1h, TLC detects, and reaction completes.Cold cut, to room temperature, is poured in water (200mL), is got organic phase, washes twice with water (2x100mL), and revolve desolventizing and obtain compound (VI) 20.72g, yield is 87.7%.
(5) preparation of compound (VIII):
500ml round-bottomed flask adds compound (VI) (20.0g, 60.39mmol), compound (VII) (13.30g, 60.39mmol) with ethanol (200mL), and stir 15min, then add salt of wormwood (16.69g, 120.79mmol), be heated with stirring to backflow 3.5h, TLC to detect, reaction completes.Reclaim ethanol, residue mixes with water (100mL) pulls an oar, and filters, uses a small amount of water washing, and dry, obtain compound (VIII) 26.12g, yield is 92.0%.
(6) preparation of Azilsartan (I):
250ml round-bottomed flask adds compound (VIII) (25g, 53.14mmol) and water (130mL), stirs, slowly add 10% sodium hydroxide solution (42.5mL, 106.28mmol), be heated to 75 DEG C of reaction 1h, TLC detection reaction complete.Be chilled to room temperature and be placed in ice-water bath, being down to 0 DEG C, slowly adding 1N hydrochloric acid under stirring to pH=3.Filter, filter cake obtains white solid through dehydrated alcohol recrystallization, is Azilsartan (I) 22.21g, yield 91.5%.
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (10)
1. one kind as shown in the formula the compound shown in A:
Wherein, X is selected from lower group: halogen; Preferably, X is Cl or Br.
2. the preparation method of formula A compound as claimed in claim 1, is characterized in that, comprise step:
(1) in inert solvent, react with formula (III) compound and halide reagent, obtain formula A compound:
In formula, X is halogen; Preferably, X is Cl or Br.
3. method as claimed in claim 2, it is characterized in that, in described step (1), described halide reagent is selected from lower group: chlorine, NCS, sulfur oxychloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, trichloroisocyanuric acid, or its combination; Preferred NCS, trichloroisocyanuric acid, or its combination.
4. the preparation method of formula A compound as claimed in claim 2, it is characterized in that, described method also comprises step:
(1a) in inert solvent, with formula (II) compound and oximate reagent react, formula (III) compound is obtained:
Preferably, described oximate reagent is selected from lower group: oxammonium hydrochloride, phosphatic hydroxylamine, hydrogen peroxide/ammonium chloride, hydrogen peroxide/ammonium acetate, or its combination; Preferred oxammonium hydrochloride, phosphatic hydroxylamine, or its combination.
5. method as claimed in claim 4, is characterized in that, in described step (1a), described reaction is carried out under alkaline catalysts exists; Preferably, described alkaline catalysts is selected from lower group: salt of wormwood, sodium carbonate, sodium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, or its combination; Preferred sodium hydroxide, potassium hydroxide, or its combination.
6. a preparation method for formula (V) compound, is characterized in that, comprise step:
(2) in inert solvent, react with formula A compound and cyanate, obtain formula (V) compound;
Wherein, the definition of X as described in the appended claim 1; Preferably, X is Cl.
7. method as claimed in claim 6, it is characterized in that, in described step (2), described cyanate is selected from lower group: potassium cyanate, Zassol, or its combination; Preferred potassium cyanate.
8. the preparation method as shown in the formula the compound Azilsartan shown in (I):
It is characterized in that, comprise step:
(2) in inert solvent, react with formula (IV) compound and cyanate, obtain formula (V) compound;
With formula (V) preparation of compounds of formula (I) compound.
9. method as claimed in claim 8, it is characterized in that, described method also comprises step:
(3) in inert solvent, react with formula (V) compound and bromide reagent, obtain formula (VI) compound;
(4) in inert solvent, react with formula (VI) and formula (VII) compound, obtain formula (VIII) compound;
(5) in inert solvent, be hydrolyzed with formula (VIII) compound, obtain formula (I) compound;
Preferably, described step (4) is carried out under base catalysis;
Preferably, described step (5) is carried out under base catalysis.
10. method as claimed in claim 9, it is characterized in that, described method also comprises step:
(1a) in inert solvent, with formula (II) compound and oximate reagent react, formula (III) compound is obtained:
(1) in inert solvent, react with formula (III) compound and chlorination reagent, obtain formula (IV) compound:
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| CN112898287A (en) * | 2020-12-31 | 2021-06-04 | 南京国星生物技术研究院有限公司 | Preparation method of azilsartan |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1585756A (en) * | 2001-11-02 | 2005-02-23 | 里格尔制药公司 | Substituted diphenyl heterocycles useful for treating HCV infection |
| CN103880830A (en) * | 2013-03-22 | 2014-06-25 | 江西同和药业有限责任公司 | Novel synthesis method of azilsartan |
-
2014
- 2014-09-04 CN CN201410449023.0A patent/CN104311453A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1585756A (en) * | 2001-11-02 | 2005-02-23 | 里格尔制药公司 | Substituted diphenyl heterocycles useful for treating HCV infection |
| CN103880830A (en) * | 2013-03-22 | 2014-06-25 | 江西同和药业有限责任公司 | Novel synthesis method of azilsartan |
Non-Patent Citations (1)
| Title |
|---|
| AHMAD Q. HUSSELN: ""Heterocycles from Nitrile Oxides. 3. 1,2,4-0xadiazol-5(4H)-ones"", 《J. CHEM. ENG. DATA》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112898287A (en) * | 2020-12-31 | 2021-06-04 | 南京国星生物技术研究院有限公司 | Preparation method of azilsartan |
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